This project has as its main goal a full understanding of the binding event, and of binding sites in proteins for at least three currently used anesthetic chemotypes, haloalkanes, haloethers and alkylphenols. This includes an understanding of the features underlying binding energetics (affinity) and selectivity, as well as a characterization of the distribution of such sites in specific proteins, like ion channels. We will accomplish these ambitious goals through two specific aims. Aim 1 is to design, synthesize and characterize novel chemical tools to discover anesthetic binding sites in complex heteroligomeric ion channel proteins. Aim 2 will deploy these tools, such as the very successful general anesthetic photolabels, in both ligand and voltage gated ion channels. This latter work both provides and directly tests hypotheses in the other projects. The long range goal is to understand features ofthe ligand and ofthe binding site that underlie selectivity so that the compounds can be altered to enhance on-pathway effects and/or to reduce off-pathway effects. Overall, project 1 is a translational conduit of program derived information to clinical relevance.